Biologically active amides

ABSTRACT

CINNAMAMIDE compounds of the formula ##STR1## where X is chloro, bromo or iodo and R is hydrogen or alkyl of 1 to 3 carbons as pharmaceuticals which are useful in the treatment or prophylaxis for convulsions.

This is a division, of application Ser. No. 596,653 filed July 17, 1975now U.S. Pat. No. 4,041,071.

This invention is concerned with new chemicals which have valuablepharmacological properties. In particular, the invention concerns novelcinnamamides, their synthesis, pharmaceutical preparations containingthem, and their use in medicine.

It has been found that the cinnamamides of formula (I), as definedbelow, have anti-convulsant activity in mammals as is shown by theireffects upon mice when administered to them in establishedpharmacological tests. These tests are:

1. Maximal Electroshock Test (MES) in mice, a method described byWoodbury and Davenport, Arch int. Pharmacodyn. Ther. 92. P. 97-107(1952).

2. Metrazol Seizure Test (MET) in mice, a method described by Swinyard,Brown and Goodman, J. Pharmacol. Exp. Therap. 106, 319-330 (1952).

In formula (I) ##STR2## X is chlorine, bromine or iodine, and R ishydrogen or alkyl having 1 to 3 carbon atoms. The trans configuration ofthe compounds of formula (I) is preferred; and the compound wherein R isethyl and X is bromine in the trans configuration has outstandinganti-convulsant activity in both pharmacological tests described above.Other examples of compounds within the scope of formula (I) include:

Trans 3-Bromo-N-methylcinnamamide

Trans 3-Bromo-N-n-propylcinnamamide

Trans 3-Bromo-N-isopropylcinnamamide

Trans 3-Chloro-N-methylcinnamamide

Trans 3-Chloro-N-ethylcinnamamide

Trans 3-Chloro-N-n-propylcinnamamide

Trans 3-iodocinnamide, trans 3-iodo-N-isopropylcinnamamide

The compounds of formula (I) may be made by any method known for thesynthesis of cinnamamides of analogous structure. For example they maybe prepared by the acylation of an amine RNH₂ (wherein R is hydrogen oralkyl having 1-3 carbon atoms) by the corresponding acid of formula(II): m--X--PhCH═CHCO₂ H (wherein X has the meaning given for formula(I)) or a reactive derivative thereof such as a thioester or an ester(e.g. an alkyl ester), an amide, an acid halide (e.g. an acid chloride)or an acid anhydride. A wide variety of reaction conditions may beemployed depending upon the nature of the acylating agent, but ingeneral the reactants may be refluxed together preferably in an inertliquid medium such as ether, benzene or toluene.

A most convenient method of synthesis is to react the acid chloride withthe appropriate amine. Preferably one equivalent of the halide should beused with two or more equivalents of the amine, but the molar excess ofthe amine may be replaced by another base such as triethylamine,pyridine, dimethylaniline, anhydrous potassium or sodium carbonate. Awide variety of polar or non-polar liquid media may be used includingwater, alkanols such as methanol, ethanol, etc., ether, dioxane,benzene, toluene, xylene, petroleum ether, cyclohexane, tetrahydrofuran,chloroform and carbon tetrachloride. A wide range of temperatureconditions may be employed, for example from -10° to the refluxtemperature of the reaction mixture.

The compounds of formula (I) may be further prepared directly from thecorresponding alcohol or aldehyde of formula (III) and (IV) at atemperature below 10° C. ##STR3## wherein X has the meaning in formula(I), by reaction with the appropriate amine RNH₂ in the present ofnickel peroxide and an inert liquid medium such as ether, benzene,tetrahydrofuran, or a petroleum hydrocarbon.

The compounds of formula (I) may also be made by the reaction of anamide of formula (V): R.NH.W wherein W is a leaving group, for example--CO.H (a formamide), --CO.alkyl (an amide), --CONH₂ (urea), --COO.alkyl(urethane having 1-4 carbon atoms in the alkyl group), with an acid offormula (II) or a reactive derivative thereof, for example the acidanhydride or halide. When the anhydride is used, a catalytic amount ofsulphuric acid is preferably included. The reactants are convenientlyheated together in a liquid medium.

In a further method for making a compound of formula (I), water, ahydrogen halide or molecular halogen is eliminated from a compound offormula (VI) ##STR4## wherein A and B are the same and each is halo orone of A and B is halo or hydroxy and the other is hydrogen, and X and Rhave the meaning given in formula (I) above. For example, theelimination of water from the α- or β-hydroxy compounds of formula (VI)may be effected by reaction with a dehydrating agent such as a base(e.g. aqueous sodium hydroxide) or concentrated sulphuric orpolyphosphoric acids. The monohalo intermediates may be treated with abase (e.g. potassium hydroxide or dimethylaniline) or merely heated torelease the hydrogen halide. The dihalo intermediates may be reduced,for example with zinc and ethanol or converted to the diiodo compoundsby treatment with potassium iodide with subsequent release of moleculariodine.

The intermediate acids of formula (II) may be made by classical organicsynthetic methods such as the Perkin synthesis, the Reformatsky reactionand the Knoevenagel condensation.

The compounds of formula (I) may be used for the treatment orprophylaxis of convulsions of mammals such as mice, dogs and cats andmore importantly of man. In particular they may be used in the treatmentof epilepsy such as grand mal, petit mal, psychomotor epilepsy and focalseizures at a dose of 2 to 200 mg/kg of body weight per day. The optimumdose of course will vary with the nature of the compound, the conditionof the patient and the route of administration, but the preferred doseis in the range of 20 to 60 mg/kg, most conveniently 30 to 50 mg/kg bodyweight, per day. Administration of the desired daily dose is preferablyin three divided doses. For example, convenient forms of administrationinclude tablets each containing from 100 to 500 mg of a compound offormula (I).

For use in medicine the compounds of formula (I) may be administered asa pure chemical but are preferably presented with an acceptable carriertherefor as a pharmaceutical composition. The carrier must of course be`acceptable` in the sense of being compatible with the other ingredientsof the composition and not deleterious to the recipient of thecomposition. The carrier may be a solid or a liquid or a mixture ofsolid and liquid substances, and is preferably formulated with acompound of formula (I) as a unit-dose composition, for example atablet, capsule or sachet for oral administration or a suppository forrectal administration. Other pharmaceutically active substances may alsobe present in compositions of the present invention, and the compositionmay be formulated by any of the well-known techniques of pharmacyconsisting basically of admixture of its components.

For oral administration, fine powders or granules of the compounds maycontain diluents and dispersing and surface active agents, and may bepresented in a draught in water or in a syrup; in capsules or cachets inthe dry state or in an aqueous or non-aqueous suspension, when asuspending agent may also be included; in tablets, preferably made fromgranules of the active ingredient with a diluent, by compression withbinders and lubricants; or in a suspension in water or a syrup or an oilor in a water/oil emulsion, when flavouring, preserving, suspending,thickening and emulsifying agents may also be included. The granules orthe tablets may be coated, and the tablets may be scored.

For parenteral administration (by intramuscular or intraperitonealinjection), the compounds may be presented in unit dose or multi-dosecontainers in aqueous or non-aqueous injection solutions which maycontain antioxidants, buffers, bacteriostats and solutes which renderthe compounds isotonic with the blood; or in aqueous or non-aqueoussuspensions when suspending agents and thickening agents may also beincluded; extemporaneous injection solutions and suspensions may be madefrom sterile powders, granules or tablets which may contain diluents,dispersing and surface active agents, binders and lubricants.

It will be understood from the foregoing description that what we willclaim in accordance with this invention comprises any novel featuredescribed herein, principally but not exclusively as follows:

a. A compound of the formula (I) ##STR5## wherein X is chlorine, bromineor iodine and R is alkyl having 1 to 3 carbon atoms except where X ischlorine and R is hydrogen.

b. A compound of the formula (I) having the trans configuration.

c. 3-Bromo-N-ethylcinnamamide.

d. The synthesis of a compound of formula (I) by any known method and inparticular the methods specifically described above and including thereaction of an acid m--X--PhCH═CHCO₂ H or a reactive derivative thereofwith a compound of the formula R.NH.W wherein W is a leaving group and Rand X have the meaning in formula (I).

e. A pharmaceutical composition comprising a compound of formula (I) asset forth on page 2 and a pharmaceutically acceptable carrier therefor.

f. A method for the treatment or prophylaxis of convulsions of a mammalcomprising the administration to the mammal of an anti-convulsanteffective, non-toxic amount of a compound of formula (I) as set forth onpage 2. The following examples illustrate the invention.

EXAMPLE 1 3-Bromo-N-isopropylcinnamamide

Trans m-bromocinnamic acid (11.4 g) in dry benzene (75 ml) was heated toreflux and then a mixture of thionyl chloride (12 g) in dry benzene (50ml) was added at such a rate as to maintain constant reflux. Thereaction mixture was heated at reflux for an additional 2 hr after theaddition of thionyl chloride. The solvent and excess thionyl chloridewere then removed under reduced pressure to give trans 3-bromocinnamoylchloride (ca. 12.3 g). A solution of the 3-bromocinnamoyl chloride intoluene (150 ml) was added dropwise with stirring to a solution ofisopropylamine (10 g) in ether (200 ml). The reaction mixture wasstirred at room temperature for one hour and then heated at reflux forone hour. The solvent and excess amine were removed under reducedpressure. The crude residue was triturated with water, filtered, andrecrystallized from ethanol-water to give white, crystalline trans3-bromo-N-isopropylcinnamamide, m.p. 85°-86° C. Elemental analysis, NMRand IR spectra all confirmed the identity of the product.

EXAMPLE 2 3-Bromo-N-ethylcinnamamide

A solution of trans 3-bromocinnamoyl chloride (12.3 g) in anhydroustoulene (150 ml) was added slowly with stirring to a solution ofethylamine (10 g) in dry ether (100 ml) at room temperature. Thereaction mixture was heated at reflux for one hour, and the solvent andexcess amine were then removed under reduced pressure. The residue wastriturated with water, filtered, and recrystallized from ethanol-waterto give trans 3-bromo-N-ethylcinnamamide, m.p. 89°-90° C., as a whitecrystalline material. NMR and IR spectra as well as elemental analysiswere consistent with the assigned structure.

EXAMPLE 3 3-Bromo-N-ethylcinnamamide

Trans m-bromocinnamic acid (14.8 g), ethanol (173 ml) and concentratedsulfuric acid (0.4 ml) were combined and heated at reflux for 15 hours.About 150 ml of the ethanol was distilled off, and the remainingsolution was poured into ice/water (140 ml). The cold mixture was madestrongly alkaline with 40% sodium hydroxide and extracted with methylenechloride (4 × 60 ml). The combined methylene chloride extract was driedover anhydrous potassium carbonate. The potassium carbonate was removedby filtration and the solvent stripped off under reduced pressure. Transethyl 3-bromocinnamate, was obtained as a partially solidified oil. (IRspectrum was consistent with this compound).

Trans ethyl 3-bromocinnamate (8.4 g), ethylamine (6.7 g), methanol (18ml) and 4A molecular sieves (1 g) were combined and heated at reflux for1/2 hour. The mixture was cooled to about 45° C and sodium methylate(0.6 g) added. The mixture was then heated at reflux 11/2 hour and thencooled. It was acidified with concentrated hydrochloric acid (12 ml).The sieves were removed by filtration. Ice water was added to thefiltrate to precipitate trans 3-bromo-N-ethylcinnamamide, m.p. 89°-90° C(after recrystallization from ethanol/water).

EXAMPLE 4 3-Bromo-N-methylcinnamamide

A solution of trans 3-bromocinnamoyl chloride (5 g) in dry benzene (100ml) was added with stirring to an ethereal (200 ml) solution ofmethylamine (3 g). After the addition was complete, a slow stream ofmethylamine gas was bubbled through the reaction mixture at roomtemperature for one hour. Solvent and excess amine were removed underreduced pressure. The crude product was triturated with water, filtered,and recrystallized from ethanol-water to give trans3-bromo-N-methylcinnamamide, m.p. 147°-147.5° C. NMR, IR, and elementalanalysis were consistent with this structure.

EXAMPLE 5 3-Chloro-N-ethylcinnamamide

Trans 3-chlorocinnamoyl chloride (4.4 g) in dry benzene (75 ml) wasallowed to react with an excess of ethylamine in dry ether (75 ml)according to the procedure of Example 2. Trans3-chloro-N-ethylcinnamamide, m.p. 87°-88° C, was obtained which had NMR,IR, and elemental analysis consistent with this structure.

EXAMPLE 5(a) 3-Iodo-N-ethylcinnamamide

Trans m-iodocinnamoyl chloride was prepared from trans m-iodocinnamicacid according to the standard procedure exemplified in Example 1. Theacid chloride (6.6 g) in dry toluene (200 ml) was added with stirring toa solution of ethylamine (3.0 g) in dry ether (300 ml) at roomtemperature. The reaction mixture was heated at reflux for one hour andthen worked up according to Example 2 to yield transm-iodo-N-ethylcinnamamide (6.4 g, 93% of theoretical), m.p. 116°-117° Cas a white, crystalline material. NMR, IR and elemental analysis wereconsistent with this structure.

EXAMPLES 6-10

Following the procedure of Example 2, the following trans compounds wereprepared (in all cases the NMR and IR spectra and elemental analysisconfirmed the structure) in which X and R have the values in formula(I):

    ______________________________________                                        Example     X       R           m.p. (° C)                             ______________________________________                                        6           Cl      CH.sub.3    124 - 125                                     7           Cl      CH.sub.2 CH.sub.2 CH.sub.3                                                                78 - 79                                       8           Br      CH.sub.2 CH.sub.2 CH.sub.3                                                                84 - 85                                       9           Br      H           107 - 108                                     10          Cl      H           81 - 82                                       ______________________________________                                    

EXAMPLE 11

A suppository was formulated from the following ingredients:

    ______________________________________                                        trans   3-Bromo-N-ethylcinnamamide                                                                          300 mg                                                  Cocoa butter         2000 mg                                          ______________________________________                                    

EXAMPLE 12

A soft gelatin capsule was filled with the following ingredients:

    ______________________________________                                        trans   3-Bromo-N-ethylcinnamamide                                                                         300 mg                                                   Lactose              75 mg                                                    Starch, corn         20 mg                                                    Fused silica         2 mg                                                     Magnesium stearate   3 mg                                             ______________________________________                                    

EXAMPLE 13

A syrup suspension was prepared from the following ingredients:

    ______________________________________                                        trans                                                                              3-Bromo-N-ethylcinnamamide                                                                             300 mg                                               Sodium carboxymethylcellulose                                                                           20 mg                                               Microcrystalline cellulose                                                                             100 mg                                               Glycerin                 500 mg                                               Polysorbate 80            10 mg                                               Flavouring agent         Q.S                                                  Preserving agent         .1%                                                  Sucrose syrup            Q.S. to 5 ml                                    ______________________________________                                    

EXAMPLE 14

A compressed tablet was prepared from the following:

    ______________________________________                                        trans   3-Bromo-N-ethylcinnamamide                                                                         300 mg                                                   Corn starch          50 mg                                                    Microcrystalline cellulose                                                                         50 mg                                                    Stearic acid         4 mg                                                     Magnesium stearate   1 mg                                                     Fused silica         1 mg                                             ______________________________________                                    

EXAMPLE 15

In the MES pharmacological test referred to hereinbefore, trans3-bromo-N-ethylcinnamamide had an oral ED₅₀ in the mouse and rat of 80mg/kg and 26 mg/kg respectively.

EXAMPLE 16

Anticonvulsant activity was determined in mice using the MaximalElectroshock Test (MES) performed according to the method of Woodburyand Davenport, supra- with corneal electrodes and a WahlquistElectroshock Stimulator Model E (manufactured by Wahlquist InstrumentCo., Salt Lake City, Utah.)

trans 3-Bromo-N-ethylcinnamamide was suspended in 0.5% aqueousmethylcellulose by homogenation in a tissue homogenization grinder togive a particle size such that greater than 51% was less than 5 micronsand greater than 87% was less than 20 microns to give concentrations of5,7.5, 10,15, and 20 mg of compound per ml of methylcellulose solution.The mice, male, ICR Blue Spruce of 22 g average weight, were dividedinto six groups of ten mice each. The trans 3-Bromo-N-ethylcinnamamidesuspensions were administered one hour prior to test orally (p.o.) bydirect injection into the stomachs of the mice. The control micereceived an equivalent volume of p.o. aqueous 0.57. methylcellulose onehour prior to test.

A current of 50 ma was applied to the cornea of the mice for 0.2 secondand the time elapsed between application of the electric shock and hindlimb extensor seizure (convulsive extension of the hind legs) measuredand recorded as latency of hind limb extension. Animals were consideredprotected (p) if the hind limb extensor component of the convulsion wasblocked. An increase over the control group in mean latencies is alsoindicative of anti-convulsant activity.

    __________________________________________________________________________            Latency of Hind Limb Extension (seconds)                              Dose, mg/kg                                                                           0 (control)                                                                         50   75   100  150  200                                         Mice in Group                                                                         Group 1                                                                             Group 2                                                                            Group 3                                                                            Group 4                                                                            Group 5                                                                            Group 6                                     __________________________________________________________________________    1       1.8   p    p    1.2  p    p                                           2       2.0   p    2.8  4.8  p    p                                           3       1.5   1.8  3.3  p    p    p                                           4       1.8   1.8  2.1  2.2  p    p                                           5       1.2   1.2  3.2  p    p    p                                           6       1.2   1.2  p    p    p    p                                           7       1.2   p    1.8  1.8  p    p                                           8       1.8   1.2  2.8  p    p    p                                           9       1.8   1.2  p    p    p    p                                           10      1.8   2.2  p    1.5  p    p                                           % protected                                                                           0     30   40   50   100  100                                         Mean Latency                                                                          1.61  1.51 2.66 2.30 --   --                                          __________________________________________________________________________

The above test results (% protected) demonstrates that trans3-Bromo-N-ethylcinnamamide is effective in preventing convulsive hindlimb extension due to electrical shock in mice.

Each group comprised 10 mice. A different group was used for eachdosage. p indicates protected against electrical shock.

What we claim is:
 1. The method of treating or preventing convulsions ina mammal which has had convulsions in the past which comprisesadministering to said mammal an effective non-toxic anti-convulsantamount of a compound trans 3-bromo-N-ethylcinnamamide.
 2. The method ofclaim 1 in which the compound is orally or parenterally administered. 3.The method of claim 2 in which the amount is 2 to 200 mg/kg of bodyweight.
 4. The method of claim 1 wherein the mammal is a human.
 5. Themethod of claim 4 is orally or parenterally administered.
 6. The methodof claim 5 in which the amount is 2 to 200 mg/kg of body weight.
 7. Themethod of treating or preventing convulsions in a mammal which has hadconvulsions in the past which comprises administering to said mammal aneffective non-toxic anticonvulsant amount of a trans compound of theformula ##STR6##
 8. The method of claim 7 in which the mammal is ahuman.
 9. The method of claim 8 in which the compound is administeredorally or parenterally.
 10. The method of claim 9 in which the amount is2 to 200 mg/kg of body weight.
 11. The method of claim 7 in which theconvulsion is a epileptic convulsion.
 12. The method of claim 4 in whichthe convulsions are epileptic convulsions.
 13. A pharmaceuticalcomposition for use as an anticonvulsant comprising an effectivenon-toxic anticonvulsant amount of a compound trans3-bromo-N-ethylcinnamamide and a pharmaceutically acceptable carriertherefore.
 14. The composition of claim 13 in unit dosage form.
 15. Thecomposition of claim 14 in which the amount is 100 to 500 mg.
 16. Thecomposition of claim 13 in a form for oral administration.
 17. Thecomposition of claim 13 in a form for parenteral administration.
 18. Thecomposition of claim 13 in the form of a suppository.
 19. Thecomposition of claim 18 wherein the composition is for the treatment orprophylaxis of epilepsy.
 20. A tablet for use as an anticonvulsant whichcomprises an effective non-toxic anticonvulsant amount of a compoundtrans 3-bromo-N-ethylcinnamamide and a pharmaceutically acceptablecarrier therefore.
 21. The tablet of claim 20 in which the amount is 100to 500 mg.
 22. A pharmaceutical preparation for use as an anticonvulsantwhich comprises an effective non-toxic anticonvulsant amount of acompound trans-3-bromo-N-ethylcinnamamide within a capsule shell. 23.The preparation according to claim 22 in which the amount is 100 to 500mg.